Cocaine abuse and its associated toxicity is clearly a major health problem today in the United States. Because of the significant incidence of severe adverse consequences associated with cocaine use there is a desperate need to develop drugs that can potentially deter the abuse of cocaine and/or protect against its acute and chronic toxicity. In order to develop and design such drugs, the cellular mechanisms of action of cocaine need to be determined. Thus, the goal of this proposal is to investigate, at the cellular level, the mechanisms by which cocaine alters the chemical interaction of neurotransmitters and neuromodulators with central neurons that have been implicated in brain reward mechanisms. A corollary of this goal is to investigate mechanisms by which cocaine may, in addition to that suggested above, after the inherent electrical activities of these same neurons. Prior research examining the action of cocaine has focused on the dopamine system. The results of that research implicate, clearly, an involvement of dopamine in the mechanism of reward resulting from cocaine use. However, dopamine is not the sole mediator responsible for the many and varied physiological and behavioral effects contributed to cocaine. This proposal will examine six different neurotransmitter/neuromodulator receptors, including dopamine, in order to clarify the mechanisms that contribute to the multiple sequelae of cocaine abuse. Neurons within the septal nuclei have been chosen to study because of their known pivotal involvement in the expression of normal and abnormal human emotions and behavior. Intracellular electrophysiological techniques, in vitro, will afford us the methodology to provide new insights into the cellular mechanisms of action of cocaine. Knowledge obtained from these experiments will provide essential information to use in the fight against acute and chronic cocaine use and toxicity.